The Efficacy of 10-day and 14-day Bismuth-based Quadruple Therapy in First-line H. Pylori Eradication

NCT ID: NCT04527055

Last Updated: 2024-06-24

Basic Information

• Recruitment Status: ENROLLING_BY_INVITATION
• Clinical Phase: PHASE4
• Total Enrollment: 312 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-06
• Study Completion Date: 2028-07-31

Brief Summary

Helicobacter pylori (H. pylori) infection is the major cause of gastritis, peptic ulcer disease, and gastric cancer in adults. Bismuth-based quadruple therapy is recommended by a recent review to be the first-line treatment for H. pylori eradication, replacing clarithromycin-based triple therapy. It is because the eradication rates of triple therapy in adults have declined due to increasing clarithromycin resistance. The best regimen for H. pylori eradication should be the one which succeeds on the first attempt. However, the effectiveness and the optimal duration of bismuth-based quadruple therapy for first-line H. pylori eradication in adults are unknown. Moreover, the impacts on gut microbiota after H. pylori eradication should be concerned; for example, bismuth-based quadruple therapy decreases F. prausnitzii richness. The transient perturbation of the gut microbiota after H. pylori eradication were restored at 8 weeks and one year in subjects receiving clarithromycin-based triple therapy but not fully recovered in those receiving bismuth-based quadruple therapy. Therefore, the important issues are that the short-term and long-term gut dysbiosis and the recovery of gut F. prausnitzii depletion in H. pylori-infected adult patients after bismuth-based quadruple therapy. It is also uncertain the role of irreversible gut dysbiosis even though H. pylori is eradicated in gastric persist inflammation and progress to cancer, and whether probiotics could be helpful in recovering gut dysbiosis.

The therapeutic strategy to eradicate H. pylori infection is based on antibiotics; however, this strategy not only increases drug resistant rates of the pathogen but also shapes the gut microbiota.

The investigators hypothesize that bismuth-based quadruple therapy could be an optimal regimen for first-line H. pylori eradication in the era of increasing clarithromycin resistance; moreover, gut dysbiosis could be reversed after bismuth-based quadruple therapy. Furthermore, the efficacy of the10-day course is not inferior to that of the 14-day course in H. pylori eradication. The investigators also hypothesize that probiotics could restore gastric or gut dysbiosis, especially gut F. prausnitzii depletion.

Detailed Description

Bismuth-based quadruple therapy is recommended by a recent review to be the first-line treatment for H. pylori eradication, replacing clarithromycin-based triple therapy. It is because the eradication rates of triple therapy in adults and clarithromycin-contained sequential therapy in children have declined due to increasing clarithromycin resistance in both adults and children. The best regimen for H. pylori eradication should be the one which succeeds on the first attempt. However, the effectiveness and the optimal duration of bismuth-based quadruple therapy for first-line H. pylori eradication in children and adults, respectively, are unknown. Moreover, the impacts on gut microbiota after H. pylori eradication should be concerned; nevertheless, the results are controversial.

Probiotic supplements are beneficial to gut health through modulation of the gut microbiota and metabolomics. Our previous studies also reported that the efficacy of H. pylori eradication is improved and relevant immune response could be modified by probiotics-containing yogurt ingestion. Our preliminary data have shown that gut F. prausnitzii depletion in H. pylori-infected children could be reversed after triple eradication therapy with probiotics-containing yogurt ingestion. However, it is uncertain whether the recovery of gut F. prausnitzii by probiotics could restore gut dysbiosis or improve systemic inflammation, and the role of gut F. prausnitzii or metabolites in the H. pylori-microbiota-host metabolism axis.

The investigators hypothesize that bismuth-based quadruple therapy could be an optimal regimen for first-line H. pylori eradication in the era of increasing clarithromycin resistance; moreover, gut dysbiosis could be reversed after bismuth-based quadruple therapy. Furthermore, the efficacy of the10-day course is not inferior to that of the 14-day course in H. pylori eradication. Among the H. pylori-infected patients, they are randomized to the 14-day bismuth-based quadruple therapy group and the 10-day bismuth-based quadruple therapy group to receive a 14-day and 10-day course, respectively, of the bismuth-based quadruple therapy, including esomeprazole (Nexium 40 mg) 1 tab twice a day, dibismuth trioxide (KCB F.C. 120 mg) 1 tab four times a day, metronidazole (Flagyl 250 mg) 2 tab thrice a day, and tetracycline (250 mg) 2 tab four times a day.

Moreover, the investigators also hypothesize that probiotics could restore gastric or gut dysbiosis, especially gut F. prausnitzii depletion. The patients who still have depletion of gut F. prausnitzii 12 months after H. pylori eradication are enrolled into the probiotic supplement trial. They are randomized to the probiotic therapy group ingesting probiotic powder twice daily for 24 weeks and the non-probiotic control group, respectively. The probiotic powder is named as "President AB powder", which contains an approximately equal mixture of Lactobacillus acidophilus and Bifidobacterium lactis Bb12 at a concentration of >= 10E9 CFU/mL (President Corp., Tainan, Taiwan)

Sample size assessment: The investigators propose that the eradication rates in the bismuth-based quadruple therapy are ~97%. The case ratio of the two groups is 1:1. If there is a true difference in favor of the 14-day bismuth-based quadruple therapy of 7% (10-day therapy vs. 14-day therapy, < 90% vs. 97%), then a total of 250 patients are required to be 90% (power) sure that the upper limit of a one-sided 97.5% confidence interval (or equivalently a 95% two-sided confidence interval) will exclude a difference in favor of the 14-day bismuth-based quadruple therapy group of more than 7% [Sealed Envelope Ltd. 2012. Power calculator for binary outcome non-inferiority trial. [Online] Available from: https://www.sealedenvelope.com/power/binary-noninferior/ [Accessed Sun Feb 14 2021]. Assuming a surveying failure rate of ~20%, at least 312 patients are needed.

In addition, the investigators propose that the rates of gut F. prausnitzii depletion before and after probiotic therapy are 50% and 25%, respectively. With a two-side alpha value of 0.05 and power of 80% (β=0.20), the number of patients required is 92 in such a paired sample. Assuming a surveying failure rate of 10%, at least 103 subjects are needed in the probiotic therapy group. Moreover, according to case ratio of the probiotic therapy group and the non-probiotic control group as 7:3, and the number required is 46 in the non-probiotic control group.

Statistical analysis: The statistical analysis is performed with SPSS software (SPSS 17, Chicago, IL, USA). The Student's t-test, Pearson's χ2 test, and Mann-Whitney U test are conducted to identify the statistical differences between the two comparison groups. One-way ANOVA with Tukey's least significant difference, Pearson's χ2 test, and Kruskal-Wallis one-way ANOVA by ranks and post hoc comparison by Mann-Whitney U test are used to identify the statistical differences between the three or more comparison groups. Paired t-test, McNemar, and Wilcoxon signed-rank test are conducted to identify the statistical differences between the pair data. All of the tests are two-tailed with the statistical significance defined as P < 0.05.

Conditions

Helicobacter Pylori Infection; Dysbiosis; Probiotics

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

The 14-day bismuth-based quadruple therapy group

The patients receive a 14-day course of the bismuth-based quadruple therapy, including esomeprazole (Nexium 40 mg) 1 tab twice a day, bismuth subcitrate (dibismuth trioxide) (KCB F.C. 120 mg) 1 tab four times a day, metronidazole (Flagyl 250 mg) 2 tab thrice a day, and tetracycline (250 mg) 2 tab four times a day.

Group Type: ACTIVE_COMPARATOR

Bismuth Subcitrate 120 MG Oral Tablet

Intervention Type: DRUG

Bismuth Subcitrate (120 MG Oral Tablet) 1 tab per oral four times per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

Esomeprazole 40mg

Intervention Type: DRUG

Esomeprazole (40 mg) 1 tab per oral twice per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

Metronidazole 250 MG

Intervention Type: DRUG

Metronidazole (250 MG) 2 tab per oral thrice per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

Tetracycline Pill

Intervention Type: DRUG

Tetracycline (250 MG) 2 tab per oral four times per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

The 10-day bismuth-based quadruple therapy group

The patients receive a 10-day course of the bismuth-based quadruple therapy, including esomeprazole (Nexium 40 mg) 1 tab twice a day, bismuth subcitrate (dibismuth trioxide) (KCB F.C. 120 mg) 1 tab four times a day, metronidazole (Flagyl 250 mg) 2 tab thrice a day, and tetracycline (250 mg) 2 tab four times a day.

Group Type: ACTIVE_COMPARATOR

Bismuth Subcitrate 120 MG Oral Tablet

Intervention Type: DRUG

Bismuth Subcitrate (120 MG Oral Tablet) 1 tab per oral four times per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

Esomeprazole 40mg

Intervention Type: DRUG

Esomeprazole (40 mg) 1 tab per oral twice per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

Metronidazole 250 MG

Intervention Type: DRUG

Metronidazole (250 MG) 2 tab per oral thrice per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

Tetracycline Pill

Intervention Type: DRUG

Tetracycline (250 MG) 2 tab per oral four times per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

The non-H. pylori-infected control

Age- and sex-matched patients who do not have H. pylori infection by endoscopic gastric biopsy are enrolled as the non-H. pylori-infected control.

Group Type: NO_INTERVENTION

No interventions assigned to this group

The probiotic therapy group

The patients who still have depletion of gut F. prausnitzii 12 months after H. pylori eradication are enrolled into the probiotic supplement trial. They are randomized to the probiotic therapy group ingesting probiotic powder twice daily for 24 weeks. The probiotic powder is named as "President AB powder", which contains an approximately equal mixture of Lactobacillus acidophilus and Bifidobacterium lactis Bb12 at a concentration of \>= 10E9 CFU/mL (President Corp., Tainan, Taiwan).

Group Type: ACTIVE_COMPARATOR

Lactobacillus acidophilus and Bifidobacterium lactis Bb12

Intervention Type: DIETARY_SUPPLEMENT

The probiotic powder per oral twice daily for 24 weeks. The probiotic powder is named as "President AB powder", which contains an approximately equal mixture of Lactobacillus acidophilus and Bifidobacterium lactis Bb12 at a concentration of \>= 10E9 CFU/mL (President Corp., Tainan, Taiwan).

The non-probiotic control group

The patients who still have depletion of gut F. prausnitzii 12 months after H. pylori eradication are enrolled into the probiotic supplement trial. They are randomized to the non-probiotic control therapy and they do not ingest probiotic powder.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Bismuth Subcitrate 120 MG Oral Tablet

Bismuth Subcitrate (120 MG Oral Tablet) 1 tab per oral four times per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

Intervention Type: DRUG

Lactobacillus acidophilus and Bifidobacterium lactis Bb12

The probiotic powder per oral twice daily for 24 weeks. The probiotic powder is named as "President AB powder", which contains an approximately equal mixture of Lactobacillus acidophilus and Bifidobacterium lactis Bb12 at a concentration of \>= 10E9 CFU/mL (President Corp., Tainan, Taiwan).

Intervention Type: DIETARY_SUPPLEMENT

Esomeprazole 40mg

Esomeprazole (40 mg) 1 tab per oral twice per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

Intervention Type: DRUG

Metronidazole 250 MG

Metronidazole (250 MG) 2 tab per oral thrice per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

Intervention Type: DRUG

Tetracycline Pill

Tetracycline (250 MG) 2 tab per oral four times per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy

Intervention Type: DRUG

Other Intervention Names

KCB F.C.; President AB powder; Nexium; Tolizole; Tetracycline (250 mg)

Eligibility Criteria

Inclusion Criteria

• Patients who are > 18 years
• Receive gastroscopy because of dyspepsia, acid regurgitation, melena, hematemesis, or others

Exclusion Criteria

• Bleeding diathesis,
• Major organic diseases
• Malignancy
• Diseases treated with chemotherapy within one month
• Diseases treated with steroids within one month
• Diseases treated with antibiotics within one month,
• Users of aspirin within four weeks before enrollment
• Users of nonsteroidal anti-inflammatory drugs within four weeks before enrollment
• Users of cyclooxygenase-2 selective inhibitors within four weeks before enrollment
• History of H. pylori eradication
• Ingest probiotics or probiotics-containing yogurt with a frequency of >= twice per week one month prior to enrollment

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cheng-Kung University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Hsiu-Chi Cheng

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hsiu-Chi Cheng, PhD

Role: PRINCIPAL_INVESTIGATOR

National Cheng-Kung University Hospital

Locations

Helicobacter pylori study group, National Cheng Kung University Hospital

Tainan City, , Taiwan

Countries

Taiwan

References

Yang EH, Chen WY, Chiang HC, Li CH, Wu IH, Chen PJ, Wu CT, Tsai YC, Cheng WC, Huang CJ, Sheu BS, Cheng HC. 10-Day versus 14-day bismuth quadruple therapy for first-line eradication of Helicobacter pylori infection: a randomised, open-label, non-inferiority trial. EClinicalMedicine. 2024 Mar 11;70:102529. doi: 10.1016/j.eclinm.2024.102529. eCollection 2024 Apr.

Reference Type: DERIVED

PMID: 38500841 (View on PubMed)

Cheng HC, Yang YJ, Yang HB, Tsai YC, Chang WL, Wu CT, Kuo HY, Yu YT, Yang EH, Cheng WC, Chen WY, Sheu BS. Evolution of the Correa's cascade steps: A long-term endoscopic surveillance among non-ulcer dyspepsia and gastric ulcer after H. pylori eradication. J Formos Med Assoc. 2023 May;122(5):400-410. doi: 10.1016/j.jfma.2022.11.008. Epub 2022 Nov 30.

Reference Type: DERIVED

PMID: 36463082 (View on PubMed)

Other Identifiers

B-BR-109-012

Identifier Type: -

Identifier Source: org_study_id